Not applicable.
Not applicable.
This invention relates to processes for fluorinating xcex2-dicarbonyls to form the corresponding xcex1-fluorinated-xcex2-dicarbonyl compounds.
Previously, xcex2-dicarbonyls, such as xcex2-diketones and xcex2-ketoesters, having the formula: 
where R1 is H, alkyl or alkoxy, R2 is H, alkyl or perfluoroalkyl, and R3 is H, Cl, Br, I or alkyl, have been fluorinated directly with fluorine in acidic solvents or in polar solvents containing acidic, or weakly basic, polar additives. See, e.g., U.S. Pat. No. 5,569,778 (Umemoto et al.) and WO 95/14646 (Chambers et al.). This technology has proven reasonably selective for those diketones and ketoesters which are stabilized in the enol form under the chosen solvent conditions. Even with substrate loadings of only 5-10 wt. %, however, the desired monofluorinated products still contain 10-15% radical fluorination impurities (the term xe2x80x9cradical fluorination impuritiesxe2x80x9d refers to products resulting from fluorination at R1 and/or R2 in Formula I above).
EP 0891962 (Nukui et al.) discloses a process for preparing fluorinated dicarbonyl compounds comprising reacting dicarbonyl compounds and fluorine gas without any solvent and in the presence of at least one acid selected from the group consisting of trifluoromethanesulfonic acid (i.e., triflic acid), methanesulfonic acid, hydrofluoric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride and sulfonated polymers. Nukui et al. discloses in Example 1 that methyl-3-oxopentanoate can be fluorinated in the absence of solvent with triflic acid as an additive, to give only 16% fluorination impurities, including 2,2-difluorinated impurity. The yield was reported to be high only when 2.5 equivalents of fluorine were added.
Ketoesters containing perfluoroalkyl groups are only effectively fluorinated in nonpolar solvents. Under these conditions, 30% radical fluorination is observed. For all of the dicarbonyl substrates, fluorinated impurities are often difficult to separate and many of them are carried forward in subsequent chemical steps.
A further problem in direct fluorinations with formic acid, trifluoroacetic acid and/or triflic acid, has been that fluorine use has been inefficient. Between 1.6 and 4 times the stoichiometric amount of fluorine has been required to obtain high conversions with these acid additives.
Accordingly, it is desired to directly fluorinate xcex2-dicarbonyl compounds by a process that does not suffer from the foregoing deficiencies in the art.
All references cited herein are incorporated herein by reference in their entireties.
The invention comprises a process for providing an xcex1-fluorinated-xcex2-dicarbonyl compound, said process comprising directly fluorinating a xcex2-dicarbonyl compound with fluorine to provide the xcex1-fluorinated-xcex2-dicarbonyl compound, wherein the direct fluorination is conducted in a reactive medium. The reactive medium preferably comprises a radical scavenger, such as oxygen, that inhibits side reactions between fluorine and acid additives.
Not applicable.
Embodiments of the invention comprise a process which uses dilute oxygen as a radical scavenger for the direct fluorination of xcex2-dicarbonyl compounds, as shown in 
where R1 is H, alkyl or alkoxy, R2 is H, alkyl or perfluoroalkyl, and R3 is H, Cl, Br, I or alkyl. The products of the inventive process (e.g., 2-fluoro-1,3-dicarbonyls) are important precursors to fluorinated heterocycles used in the pharmaceutical industry.
Conventional processes of direct fluorination typically provide fluorinated carbonyl products which are only 75-85% pure and contaminated with radical fluorination byproducts, which are difficult to separate. Use of oxygen in the fluorine stream can lightly lower the overall isolated yield, but after washing with water, yields a product which is 90-96% pure and containing radical fluorination impurity levels which are 5-20% lower than when oxygen is not used. Use of oxygen in the fluorine stream inhibits side reactions between fluorine and acid additives used in direct fluorination (e.g., formic acid, trifluoroacetic acid, and/or triflic acid) so that less fluorine is required to give high substrate conversion.
In embodiments of the inventive process, F2/N2 mixtures are diluted with air to give dilute F2/O2/N2 mixtures, which are sparged into solutions of the substrate in an acidic solvent (for ketoesters where R2=Rf, the solvent is CFCl3). The gas mixture can suitably comprise about 1 to about 50% F2, about 0.1% to about 50% O2 and about 0 to about 99% N2, preferably about 5 to about 25% F2, about 1 to about 25% O2 and about 50 to about 95% N2, more preferably about 10 to about 20% F2, about 10 to about 20% O2 and about 60 to about 80% N2. At high conversions, less than 5% radical fluorination byproducts are observed.
Surprisingly, when oxygen is added during the fluorination, ketoesters (where R2=Rf) can be fluorinated selectively without a solvent. When fluorinated neat in the absence of oxygen, these compounds char, giving only a small amount of the desired product. The process, therefore, offers the advantage of significantly higher product purity obtained at much higher reaction loadings.